sr-142801 and Asthma

Gastro-oesophageal reflux is a common clinical disorder associated with a variety of respiratory symptoms, including chronic cough and exacerbation of asthma. In this study, the potential role of acid-induced tachykinin release was examined in guinea pigs and rabbits, by examining the effects of the tachykinin NK1 and NK3 receptors antagonists (SR 140333 and SR 142801, respectively) (1-10 mg x kg(-1)) on plasma protein extravasation induced in airways by hydrochloric acid (HCl) infusion in the oesophagus. Guinea pigs were anaesthetised with urethane, while rabbits were subject to neuroleptoanalgesia with hypnorm. Airway vascular leakage was evaluated by measuring extravasation of Evans blue dye. All animals were pretreated with atropine (1 mg x kg(-1) i.p.), propranolol (1 mg x kg(-1) i.p.), phosphoramidon (2.5 mg x kg(-1) i.v.) and saline or tachykinin receptor antagonists (1-10 mg x kg(-1) i.p.). Infusion of 1 N HCl into the oesophagus led to a three- and five-fold increase in plasma extravasation in the main bronchi and trachea, respectively. This increase was largely prevented by the tachykinin NK1 and NK3 receptor antagonists SR 140333 and SR 142801 (1-10 mg x kg(-1)). These results suggest that protein extravasation in the airways, as induced by intraoesophageal HCl infusion, is mainly dependent on the release of tachykinins, and that both NK1 and NK3 tachykinin receptors are involved. The results suggest that HCl-induced sensory nerve stimulation may act in the periphery on intermediate neurons and/or ganglia where NK3 receptors have been shown to play an important role.

Topics: Animals; Asthma; Capillary Permeability; Disease Models, Animal; Esophagus; Female; Gastroesophageal Reflux; Guinea Pigs; Hydrochloric Acid; Instillation, Drug; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rabbits; Receptors, Neurokinin-1; Receptors, Neurokinin-3

Several observations suggest that tachykinins (substance P, neurokinin A and neurokinin B) are involved in the pathogenesis of pulmonary diseases and elicit several airway responses such as bronchoconstriction and neurogenic inflammation via interactions with specific receptors denoted NK(1), NK(2) and NK(3). We have investigated the effect of a selective antagonist for tachykinin NK(3) receptor, SR 142801 ((R)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl-N-methylacetamide), on the inflammatory cell recruitment in ovalbumin-sensitized and -challenged mice used as a model of allergic asthma. Twenty hours after the two-ovalbumin challenges, differential cell counts were calculated and indicated that SR 142801 caused a significant decrease in the number of neutrophils and eosinophils. Forty hours after the last ovalbumin exposure, SR 142801 induced a significant decrease in the recruitment of eosinophils. These results suggest that tachykinins and tachykinin NK(3) receptors can interfere with cell recruitment in inflammatory response.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophils; Lymphocytes; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Piperidines; Receptors, Neurokinin-3